U.S. patent application number 13/319901 was filed with the patent office on 2012-04-05 for method for preparing a pharmaceutical formulation of lanthanide chelate in powder form.
This patent application is currently assigned to GUERBET. Invention is credited to Marc Port.
Application Number | 20120082624 13/319901 |
Document ID | / |
Family ID | 41119495 |
Filed Date | 2012-04-05 |
United States Patent
Application |
20120082624 |
Kind Code |
A1 |
Port; Marc |
April 5, 2012 |
METHOD FOR PREPARING A PHARMACEUTICAL FORMULATION OF LANTHANIDE
CHELATE IN POWDER FORM
Abstract
The present invention relates to a method for preparing a
pharmaceutical formulation of lanthanide chelate in powder form,
this powder comprising a mol/mol excess of free chelate of between
0.002 and 0.4%, said method comprising the following successive
steps: 1) step 1: mixing the chelate and the lanthanide so as to
obtain complexation of the lanthanide by the chelate, the
complexation solution obtained comprising, in addition to the
chelate-lanthanide complex, an excess amount X1 of free chelate; 2)
step 2: preferably measuring X1; 3) step 3: precipitating the
complexation solution obtained in step 1) from an organic solvent
so as to obtain a powder of chelate-lanthanide complex, the powder
containing an excess amount X2 of free chelate; 4) step 4:
optionally adjusting X2 so as to obtain: 4.a) X2 is between 0.002
and 0.4%, and more especially between 0.02 and 0.3% mol/mol, very
advantageously between 0.025 and 0.25% mol/mol, 4.b) X2 corresponds
to between 0.2 and 2 times X1, in particular between 0.5 and 1.5
times X1, X2 advantageously belonging to the range:
[0.5-0.95].times.X1, or to the range [1.05-1.3].times.X1; 5) step
5: preferably measuring X2.
Inventors: |
Port; Marc; (Deuil la Barre,
FR) |
Assignee: |
GUERBET
Villepinte
FR
|
Family ID: |
41119495 |
Appl. No.: |
13/319901 |
Filed: |
May 12, 2010 |
PCT Filed: |
May 12, 2010 |
PCT NO: |
PCT/EP2010/056603 |
371 Date: |
December 21, 2011 |
Current U.S.
Class: |
424/9.363 |
Current CPC
Class: |
A61K 49/108 20130101;
A61K 49/06 20130101; A61K 9/08 20130101 |
Class at
Publication: |
424/9.363 |
International
Class: |
A61K 49/10 20060101
A61K049/10 |
Foreign Application Data
Date |
Code |
Application Number |
May 13, 2009 |
FR |
0953147 |
Claims
1. Method for preparing a pharmaceutical formulation of lanthanide
chelate in powder form, this powder comprising a mol/mol excess of
free chelate of between 0.002 and 0.4%, said method comprising the
following successive steps: 1) step 1: mixing the chelate and the
lanthanide so as to obtain complexation of the lanthanide by the
chelate, the complexation solution obtained comprising, in addition
to the chelate-lanthanide complex, an excess amount X1 of free
chelate; 2) step 2: preferably measuring X1 and optionally
adjusting X1 so as to have X1 between 0.002 and 0.4% mol/mol; 3)
step 3: precipitating the complexation solution obtained in step 1)
from an organic solvent so as to obtain a powder of
chelate-lanthanide complex, the powder containing an excess amount
X2 of free chelate, 4) step 4: optionally adjusting X2 so as to
obtain: 4.a) X2 is between 0.002 and 0.4%, and more especially
between 0.02 and 0.3% mol/mol, very advantageously between 0.025
and 0.25% mol/mol, 4.b) X2 corresponds to between 0.2 and 2 times
X1, in particular between 0.5 and 1.5 times X1, X2 advantageously
belonging to the range: [0.5-0.95].times.X1, or to the range
[1.05-1.3].times.X1; 5) step 5: preferably measuring X2.
2. Method according to claim 1, wherein step 1) is carried out in a
single step or in several successive steps by measuring and
adjusting, so as to have an amount X1 of free chelate, step 1)
advantageously comprising the following successive substeps: 1.1)
complexation in solution of the lanthanide by the chelate 1.2)
measuring the chelate and/or the lanthanide that is free 1.3)
adding free chelate, so as to complex the free lanthanide if any
remains at the end of step 1.1), and to obtain an amount X1 of free
chelate.
3. Method according to claim 1 or 2, wherein the powder obtained in
step 3) is returned to solution so as to form a pharmaceutical
composition in liquid form.
4. Method according to claim 1, wherein the lanthanide chelate is
the DOTA-Gd complex.
5. Method according to claim 1, wherein the solvent of step 3) is
chosen from ethanol, methanol and propanol.
6. Method according to claim 1, wherein the solvent of step 3) is
used according to a ratio of from 10 to 20 volumes of solvent per
volume of complexation solution.
7. Method according to claim 1, wherein the solvent of step 3) is
used at a temperature included in the range [0; 80.degree. C.],
advantageously in the range [30; 70.degree. C.].
8. Method according to claim 1, wherein the lanthanide chelate is a
macrocyclic chelate of lanthanide.
9. Method according to claim 1, wherein the complexation solution
of step 1 is a solution of [DOTA-Gd] meglumine salt.
Description
[0001] The invention relates to an industrially effective method
for preparing pharmaceutical formulations of paramagnetic metal ion
chelates, and to the use of these formulations for preparing
contrast agents for magnetic resonance imaging.
[0002] Numerous contrast agents based on lanthanide (paramagnetic
metal) chelates, in particular gadolinium chelates, described for
example in document U.S. Pat. No. 4,647,447, are known. Several
products are sold, in particular macrocyclic chelates, such as DOTA
(1,4,7,10-tetraazacyclododecane-N,N',N'',N'' -tetraacetic acid)
gadoterate and gadoteridol HPDO3A, and linear chelates such as DTPA
(diethylenetriaminepentaacetic acid) and DTPA-BMA
(gadodiamide).
[0003] In the body, lanthanide chelates are in a situation of
chemical equilibrium, which may lead to a risk of undesired release
of lanthanide, and more especially of gadolinium. Those skilled in
the art are thus led to seek solutions that limit this risk in
order to solve the complex problem of tolerance in the patient
completely safely. This problem is all the more difficult since the
administration of contrast agents is often repeated during
diagnostic examinations and/or for guiding and monitoring the
efficacy of a therapeutic treatment.
[0004] Several approaches for improving the tolerance of gadolinium
chelates are described in the prior art. More than twenty years
ago, in particular through document U.S. Pat. No. 5,876,695, those
skilled in the art worked on formulations comprising an excess of
chelate in addition to the lanthanide-complexing chelate. This
excess is intended to compensate for an undesired release of the
lanthanide, the excess chelate then complexing with the released
lanthanide (Gd3+ metal ion). Document U.S. Pat. No. 5,876,695
describes in particular an excess of linear chelate, in particular
of free DTPA. Documents EP 450 078, U.S. Pat. No. 5,876,695 and
U.S. Pat. No. 2004/0170566 in particular describe the use of
excipients written in the form X[X',L] where X' is a metal (in
particular calcium) cation complexed by the chelate, and X is a
metal cation used to obtain an uncharged salt of the complex [X',L]
(negatively charged otherwise). X and X' are typically chosen
independently of one another from sodium, zinc, magnesium and
calcium ions, L representing the chelate. This excipient therefore
makes it possible to add excess chelate.
[0005] Despite all these prior art studies, the complex problem of
tolerance still exists, especially in situations with a more
pronounced tolerance risk for the administration of MRI contrast
products. A new problem has, moreover, recently appeared in terms
of tolerance, namely a pathological condition known as NSF
(nephrologic systemic fibrosis, or fibrogenic dermopathy), which
might be correlated at least partly with the existence of
gadolinium in the body. This disease has led to health authorities
being alerted with respect to marketed gadolinium-based contrast
agents for certain categories of patients.
[0006] In fact, this problem of tolerance of lanthanide chelates
remains complex and considerable.
[0007] The applicant has shown, in the pending application
FR0851055, the importance of and the difficulty in obtaining, on
the industrial scale, for macrocyclic chelates, and in particular
DOTA, formulations comprising an excess of free chelate and in a
narrow and precise concentration range [0.002 to 0.4%] mol/mol, and
in particular 0.025 to 0.25%. The term "free chelate" refers to a
chelate not complexed by a lanthanide or a metal cation, therefore,
contrary to the prior art, not in the form of an excipient of
formula X[X',L] with X, X' and L as defined above. In order to
solve this problem, the applicant has succeeded in developing a
method for preparing a formulation of macrocyclic chelate,
preferably DOTA, DO3A, HPDO3A or PCTA, more preferably DOTA, said
method comprising at least one step of adjusting the amounts
between the chelate and the lanthanide so as to obtain, in the
final pharmaceutical solution (typically liquid injected into the
patient), a mol/mol excess of chelate between 0.002 and 0.4%, and
more especially between 0.02 and 0.3%, very advantageously between
0.025 and 0.25%.
[0008] The method described in this document advantageously
comprises the following steps: [0009] 1) mixing the chelate and the
lanthanide so as to obtain complexation of the lanthanide by the
macrocyclic chelate, typically under hot conditions (advantageously
between 60 and 90.degree. C., preferably around 80.degree. C.);
[0010] 2) measuring the amounts of free chelate and/or of
lanthanide in the solution obtained in step 1); [0011] 3) adjusting
the amounts of chelate and/or of lanthanide.
[0012] Steps 2 and 3 are performed by any suitable means after
having carried out the complexation.
[0013] Typically, an amount of chelate or of lanthanide is added so
as to achieve the target concentration of free entities, typically
of free DOTA. At the end of step 3), an adjusted pharmaceutical
solution typically in liquid form, comprising the complex, in
particular DOTA-Gd, and an excess of free chelate, in particular
free DOTA (0.1 to 0.2%, for example), is thus obtained.
[0014] At the end of step 3, either this adjusted formulation in
liquid form is the solution injected into the patient (where
appropriate after addition of pharmaceutical excipients to this
solution), or this adjusted formulation in liquid form is converted
(typically by evaporation, freeze-drying, concentration or
spray-drying) into a powder which may be returned to solution
(where appropriate with addition of pharmaceutical excipients to
this solution) to be injected into the patient.
[0015] It is recalled that many embodiment variants are included in
the scope of the pending application FR0851055.
[0016] According to one of these variants, the excipient of the
final formulation administered to the patient is added to the
adjusted pharmaceutical solution obtained after complexation (step
1) above), this excipient being advantageously meglumine for
DOTA-Gd. The liquid adjusted pharmaceutical solution thus obtained
is ready to be administered to the patient. For DOTA for example,
the solution administered contains the DOTA-Gd complex and a slight
excess of free DOTA.
[0017] According to another variant, this pharmaceutical solution
obtained after complexation is converted into a powder, so as to
obtain this adjusted formulation in the form of a powder. For DOTA
for example, this powder contains the DOTA-Gd complex and the
slight excess of free DOTA targeted. If the formulation excipient
(meglumine, for example) was introduced from the beginning of or
shortly after the complexation, and before the conversion into
powder, a powder which contains the complex and the excipient is
obtained. The meglumine salt of gadoteric acid DOTA-Gd is thus
obtained as a powder, this powder containing DOTA-Gd and free DOTA
in excess in the targeted value range.
[0018] According to another variant, the adjusted pharmaceutical
solution resulting from the complexation is converted into a
material of powder type, by any suitable method, this powder
subsequently being returned to solution with, firstly, an optional
further adjustment by adding free DOTA to this solution for example
and secondly, an addition of the formulation excipient, this
excipient being advantageously meglumine for DOTA-Gd. A final
liquid solution ready to be administered to the patient is
obtained.
[0019] Among the industrial methods for preparing a powder, the
applicant has now studied more closely the method of adjustment in
the case of precipitation. Indeed, the method by precipitation in a
solvent or a mixture of solvents is advantageous for an industrial
production.
[0020] Those skilled in the art deduce directly from the text and
the examples of FR0851055 that the solution obtained at the end of
step 1) or at the end of step 3) can be precipitated, from a
suitable organic solvent, so as to obtain a powder which may itself
be returned to solution, this solution being injected into the
patient. As described in the pending application FR0851055, the
proportions, in the powder, of DOTA-Gd and of free DOTA are
typically the same between, on the one hand, the adjusted solution
and, on the other hand, the powder.
[0021] It so happens that, by carrying out tests, the applicant has
now noted that the precipitation poses an additional problem of
optimization on the industrial batch scale, given the amounts and
the solvents used. More specifically, the applicant has noticed
that the conversion, by precipitation, of the liquid solution S
obtained in step 1 or at the end of step 3), of the method
described in FRO851055, into a powder P is typically accompanied by
a modification of proportions of the entities, between, on the one
hand, this pharmaceutical solution S and, on the other hand, the
powder P, with regard to the following entities: [0022] i) the
complexed chelate (DOTA-Gd complex, for example), [0023] ii) the
free chelate (free DOTA, for example) as defined above.
[0024] In order to control the method by precipitation, and in
particular to be sure that the pharmaceutical formulation solution
to be administered contains the target excess amount of free
chelate (free DOTA in particular, from 0.002% to 0.4%), the
applicant has developed a method for preparing a pharmaceutical
formulation of lanthanide chelate (advantageously of macrocyclic
chelate of lanthanide) (with or without pharmaceutical excipient
such as meglumine) in power form, this powder comprising a mol/mol
excess of free chelate of between 0.002 and 0.4%, said method
comprising the following successive steps: [0025] 1) step 1: mixing
the chelate (advantageously the macrocyclic chelate) and the
lanthanide so as to obtain complexation of the lanthanide by the
chelate, the complexation solution obtained comprising, in addition
to the chelate-lanthanide complex, an excess amount X1 of free
chelate; [0026] 2) step 2: preferably measuring X1, and optionally
adjusting X1 so as to have X1 between 0.002 and 0.4% mol/mol;
[0027] 3) step 3: precipitating the complexation solution obtained
in step 1) from an organic solvent so as to obtain a powder of
chelate-lanthanide complex, the powder containing an excess amount
X2 of free chelate, [0028] 4) step 4: optionally adjusting X2 so as
to obtain: [0029] 4.a) X2 is between 0.002 and 0.4% mol/mol, and
more especially between 0.02 and 0.3% mol/mol, very advantageously
between 0.025 and 0.25% mol/mol, and [0030] 4.b) X2 corresponds to
between 0.1 and 5 times X1, advantageously between 0.2 and 2 times
X1, in particular between 0.5 and 1.5 times X1; [0031] 5) step 5:
preferably measuring X2.
[0032] For the purpose of the present invention, the term "free
chelate" is intended to mean any chelate not complexed with a
lanthanide or a metal cation, therefore, contrary to the prior art,
not in the form of an excipient of formula X[X',L] with X, X' and
Las defined above.
[0033] Step 4) of adjusting X2 can be carried out by adding or
removing free chelate by any suitable means (resin, for example),
or by adding or removing lanthanide.
[0034] Advantageously, X2 belongs to the ranges:
[0035] 1) [0.1-0.95].times.X1 (X2 corresponds to between 0.1 and
0.95 times X1), even more advantageously [0.2-0.95].times.X1,
particularly [0.5-0.95].times.X1, more particularly
[0.6-0.9].times.X1, or
[0036] 2) [1.05-5].times.X1 (X2 corresponds to between 1.05 and 5
times X1), even more advantageously [1.05-2].times.X1, in
particular [1.05-1.5].times.X1, even more particularly
[1.05-1.3].times.X1.
[0037] According to embodiments, the solvent of step 3) is chosen
from: ethanol, methanol, propanol, isopropanol, methyl ethyl
acetone, ethyl acetate, and mixtures thereof (including
water/solvent in any proportions) known to those skilled in the
art, advantageously ethanol, methanol and propanol.
[0038] According to embodiments, the solvent of step 3) is used
according to a ratio of from 5 to 20 volumes of solvent per volume
of complexation solution, advantageously 10 to 20 volumes of
solvent per volume of complexation solution.
[0039] According to embodiments, the solvent of step 3) is used at
a temperature included in the range [0-80.degree. C.], in
particular between 30 and 70.degree. C.
[0040] According to embodiments, a partial concentration of the
complexation solution is performed (for example by evaporation),
before carrying out step 3) of precipitating from the solvent.
[0041] According to embodiments, the pH of the complexation
solution used in step 3) is between 1 and 9.
[0042] Advantageously, the following conditions will be used during
step 3): pH: [2-8]
[0043] [ethanol solvent]: 10 to 20 volumes per volume of
complexation solution
[0044] Temperature: [0; 50] .degree. C.
[0045] Advantageously, the powder obtained in step 3) or in step 4)
is returned to solution so as to form a pharmaceutical composition
in liquid form.
[0046] Step 1 preferably uses an excess chelate, advantageously of
DOTA, relative to the stoichiometric proportions, so as to obtain
an amount X1 of free chelate, advantageously of free DOTA.
[0047] Step 1 can be carried out in a single step or optionally in
several successive steps by measuring and adjusting so as to have
an amount X1 of free chelate, advantageously of free DOTA
(preferably between 0.002 and 0.4% mol/mol). For example, step 1)
comprises the following successive substeps: [0048] 1.1.
complexation in solution [0049] 1.2. measuring the chelate,
advantageously the DOTA, and/or the lanthanide that is free
(advantageously Gd) [0050] 1.3. adding chelate, advantageously
DOTA, so as to complex the possible free lanthanide (if there is
any at the end of step 1) and to obtain an amount X1 of free
chelate, advantageously of free DOTA (preferably between 0.002 and
0.4% mol/mol).
[0051] For the purpose of the present invention, the term "free
lanthanide" is intended to mean any lanthanide that is not
complexed and in particular not complexed by the chelate.
[0052] This variant with step 1.1 to 1.3 is advantageous since the
isolation of a powder makes it possible to be able to purify the
product.
[0053] Advantageously, the lanthanide complex is the DOTA-Gd
complex.
[0054] Thus, the controlling of the precipitation step coupled with
the prior measuring of the amount X1 of free chelate,
advantageously free DOTA, provides an adjustment of the level of
chelate, advantageously of DOTA, making it possible to solve the
problems addressed by the invention.
[0055] Typically, the detailed measurements will be carried out for
each industrial production batch. It will also be possible,
provided that the characterization of the products used is
completely controlled, to construct a calibration reference matrix
obtained by virtue of the measuring and adjusting step(s) described
in the application.
[0056] It is clear for those skilled in the art that optimization
substeps can be inserted between these main steps.
[0057] The precipitation in step 3) can be carried out by adding
the solvent to the complexation solution, or conversely by adding
the complexation solution to the solvent.
[0058] Advantageously, the powder obtained after precipitation
(step 3) is subsequently returned to solution, firstly, with or
without optional further adjustment by adding free chelate (DOTA,
for example) to this solution, and secondly, with an optional
addition of formulation excipient, this excipient being
advantageously meglumine for DOTA-Gd. A final liquid solution ready
to be administered to the patient is obtained. If meglumine has
been introduced into the complexation solution at the start, the
powder will comprise DOTA-Gd, excess free DOTA, and meglumine
[0059] According to one embodiment, the solution of step 1 does not
comprise the positive counterion (typically meglumine or the Na
ion). Step 3 will thus consist in precipitating not DOTA-Gd in
salt, typically sodium salt, or meglumine form (more specifically,
[DOTA]Gd].sup.-,Na.sup.+ or [DOTA-Gd].sup.-,
CH.sub.2OH--(CHOH).sub.4--CH.sub.2--N.sup.+--CH.sub.3), but its
protonated form [DOTA-Gd].sup.-,H.sup.+, this step being carried
out in an acidic medium.
[0060] According to another embodiment, which is moreover
advantageous and not described in the prior art, the solution of
step 1 comprises the positive counterion (meglumine in particular);
step 3 thus consists in precipitating, according to suitable
conditions (in particular of pH and of amount of solvent), the
DOTA-Gd meglumine salt [[DOTA-Gd].sup.-,
CH.sub.2OH--(CHOH).sub.4--CH.sub.2--N.sup.+--CH.sub.3]. For this,
10 to 20 volumes, for example 10 to 15 volumes, of ethanol or
methanol solvent, per complexation volume, are for example used,
advantageously at a pH between 5 and 8 and a temperature of
25-60.degree. C. This makes it possible to use a DOTA-Gd complex in
salt form, which is more stable than the protonated form (owing to
the complexation constants).
[0061] To this effect, the invention also relates to a method as
described above in the application, the complexation solution of
step 1 being a solution of DOTA-Gd meglumine salt or sodium salt,
the [DOTA-Gd] complex not being in its protonated form in this
solution. Very preferably, the complexation solution of step 1 is a
solution of [DOTA-Gd] meglumine salt, which has the advantage,
compared with a solution of DOTA-Gd sodium salt, when a meglumine
formulation that is advantageous for the patient from the tolerance
point of view is prepared, of not having to subsequently replace
the sodium with meglumine, this being an operation that is
industrially complex.
[0062] The invention also relates to the use of a powder obtained
by means of the method of the applicant, for preparing a liquid
pharmaceutical formulation comprising a mol/mol excess of free
chelate of between 0.002 and 0.4%.
[0063] The invention also relates to a method for preparing a
liquid pharmaceutical formulation comprising a mol/mol excess of
free chelate of between 0.002 and 0.4%, said method comprising the
following successive steps: [0064] a) obtaining a powder according
to the precipitation method of the present invention, [0065] b)
putting the powder obtained in step a) into solution, with, where
appropriate, the addition of at least one formulation excipient
and, where appropriate, the addition of additional free
chelate.
[0066] Moreover, it is specified that the method by precipitation
of the present application includes the method described, and
optional variants (particular variants of crystallization methods,
for example) which are reflected by a modification of the
proportions of the complexed-chelate and free-chelate entities
between, on the one hand, the pharmaceutical composition in liquid
solution form and, on the other hand, the pharmaceutical
composition in powder form.
[0067] Detailed examples are now described, illustrating the method
for preparing lanthanide chelate formulations with a precipitation
step, and more particularly the preparation by precipitation of
formulations comprising an excess chelate for DOTA.
[0068] The following table indicates an example of the amounts used
for producing a solution of 100 litres of DOTA (industrial
amount).
TABLE-US-00001 Component Amount DOTA (1) 20.100 kg (i.e. 0.497 M)
Gadolinium oxide (expressed as 9.135 kg (i.e. 0.252 M) anhydrous
product) Gd.sub.2O.sub.3 Meglumine (expressed as anhydrous 9.215 kg
product) Solution for adjustment of DOTA at 15% 15-35 mg per 100 ml
(w/v) qs level of free DOTA Solution of meglumine at 2 N qs pH =
6.8-7.4 at 20.degree. C. Injectable water . . . qs 100 litres (1)
1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid
[0069] Step 1.1: Complexation in Solution
[0070] The DOTA and the gadolinium oxide are dispersed in
injectable water at approximately 80.degree. C. The gadolinium
oxide in the presence of DOTA forms a complex-acid that is soluble
in water.
[0071] 40 litres of injectable water at 80.degree. C. are placed in
a 100 litre production tank, the injection of nitrogen is started,
and then the 20.100 kg of DOTA and the 9.135 kg of gadolinium oxide
are incorporated with stirring. The complexation is carried out at
a pH below 6.
[0072] Steps 1.2. and 1.3.: Adjustment of the Free Entities
[0073] The adjustment of the solution is advantageously carried out
with gadolinium oxide or DOTA.
[0074] At the end of step 1.1, the following steps are carried out:
[0075] 1.2. taking a sample and assaying the free gadolinium,
[0076] 1.3. adding a solution for adjustment of DOTA, quantity
sufficient for an amount of 15-35 mg per 100 ml.
[0077] A complexation solution S with a level X1 of free chelate
that can be measured (step 2) is obtained. It is also possible to
remove any residual gadolinium by virtue of a chelex resin for
example prerinsed with water (a quantification of the free
gadolinium can be carried out by means of a colorimetric assay with
Arsenazo (III) before this removal, and optionally also
afterwards). For this, the reaction mixture can be brought back to
pH 5 (the resin is more effective). The whole mixture is left to
stir at ambient temperature for 2 hours. The pH rises again to
between 6.5 and 7. The resin is removed by filtration.
[0078] The value X1 (as a percentage mol/mol) is, according to
batches, for example between 0.005 and 0.1%, in particular 0.01 and
0.05% mol/mol of free DOTA (DOTA not complexed by Gd, nor by
cations such as Ca.sup.2+).
[0079] Step 3: Precipitation of the Complexation Solution
[0080] The solution obtained in step 2 can be directly added to the
solvent, but, in order to reduce the amounts of solution to be
treated, a prior concentration under vacuum is typically carried
out without significant modification of the level of free DOTA.
[0081] The aqueous solution of DOTA-Gd is concentrated under vacuum
at a temperature below 80.degree. C. (for example between 20 and
60.degree. C., for example 50 to 70.degree. C.) to a concentration
of 0.5 kg (+/-0.2 kg) per kg of solution. The solution is cooled to
ambient temperature.
[0082] For an amount of 1 kg of concentrated solution, a solution
of 5 to 20 litres (preferably 10 to 20 litres, and typically 20
litres) of ethanol is added to 1 kg of concentrated solution. The
precipitated DOTA-Gd obtained is filtered off, and then taken up
with 3-4 litres of ethanol.
[0083] Related back to an industrial amount of 100 kg of DOTA-Gd
solution, an amount of about 2000 litres of ethanol will thus, for
example, be used to carry out the precipitation.
[0084] The product obtained is dried under vacuum at a temperature
below 80.degree. C.
[0085] The following denatured ethanol is, for example, used: 95%
ethanol, 5% mixture of ethyl acetate and isopropanol.
[0086] The compound obtained by precipitation (powder) contains an
amount X2 of free chelate. According to the solvents used, an
amount X2 (as a percentage mol/mol) which varies according to the
tests, for example, between 0.02% and 0.15% mol/mol, is
obtained.
[0087] Moreover, the results are not always identical depending on
whether the precipitation is carried out from a solution of DOTA-Gd
(with excess X1 of free DOTA) with meglumine, or from a solution of
DOTA-Gd (with excess X1 of free DOTA) without meglumine, wherein
the meglumine is to be taken into account from the point of view of
the solubilization.
[0088] Step 2a Optional After Step 2 and Before Step 3: Cooling
[0089] The final solution of step 2 is cooled to 30.degree. C., for
example by circulation of cold water in the jacket of the tank.
[0090] Step 2b Optional After Step 2a and Before Step 3: Adjustment
of the pH and of the Density
[0091] The acid function of the complex formed is salified with
meglumine and the pH at 20.degree. C. is adjusted to 6.8-7.4. The
concentration is adjusted by adding injectable water.
[0092] The following are placed in the production tank:
[0093] 9.125 kg of meglumine
[0094] and a solution of meglumine at pH =7.3-7.4 at 2 N
[0095] and qs injectable water.
[0096] Step 5 After Step 3 or 4:
[0097] The precipitated product in powder form obtained is returned
to a pharmaceutical aqueous solution (typically comprising
meglumine), subsequently filtered, and then placed in vials that
are typically sterilized by autoclaving.
* * * * *